Molecular mechanisms for exacerbation-prone asthma are poorly understood. While a critical role for Type-2 (T2) cytokines is emerging, only 20-25% of T2-Hi patients persistently exacerbate, suggesting additional factors modulate the risk. Our group recently showed (Cell, 2017) that binding of the T2-enzyme, 15 lipoxygenase 1 (15LO1) to a scaffolding protein, phosphatidyl- ethanolamine (PE) binding protein (PEBP)1, triggers a form of programmed cell death termed ferroptosis, when it switches the preferred 15LO1 substrate from free polyunsaturated fatty acids (PUFA), to PUFAs conjugated to PE, specifically 15 hydroperoxyeicosaetetranoic acid-PE (15 HpETE-PE), which drive ferroptotic cell death. Glutathione peroxidase (GPX)4, an enzyme highly sensitive to oxidative stress, rapidly converts 15 HpETE-PE to its stable hydroxy-metabolite, 15 hydroxyeicosaetetranoic acid (15 HETE)-PE preventing cell death. PEBP1 also binds the autophagy protein, microtubule light chain-3 (LC3), limiting autophagy. Expanding on this, we observed IL-13 stimulated LC3 lipidation and lowered mitochondrial numbers in human airway epithelial cells (AECs), all through 15LO1/15HpETE-PE-processes, suggesting concomitant engagement of mitophagy. These effects associate with high 15LO1-dependent intracellular oxidative stress and are also seen in airway AECs from exacerbation- prone asthma. Thus, in the presence of a ?T2/IL-4/-13 1st hit?, a pro-ferroptotic 15LO1-PEBP pathway is activated, but potentially limited to a localized disruptive mitochondrial process in association with initiation of autophagy/mitophagy (without cell death). This GSH-dependent process generates oxidatively vulnerable cells with increased secretory marker expression and lower proliferation consistent with cell senescence. With an ?oxidative 2nd hit?, GSH falls, lowering GPX4 activity and initiating generalized ferroptosis, disrupting epithelial barriers, increasing pro-inflammatory factor release and promoting exacerbations. Thus, we hypothesize that 15LO1 and PEBP1, with both GPX4 and LC3, fundamentally regulate the balance between ferroptosis and mitophagy, influencing cell function, asthma control and exacerbations. Using in vitro and ex vivo human cells and in vivo animal models we will: 1) Identify the mechanisms by which a T2?associated 1st hit? induces ?stressed homeostasis? in asthmatic airway cells, and its implications for asthma severity and control and 2) define mechanisms by which an ?oxidative 2nd hit? disrupts the ?stressed homeostasis? to induce widespread ferroptosis and promote asthma exacerbations. Thus, we will examine fundamental death and survival pathways in relation to asthma and determine whether 15LO1-PEBP activity and ferroptosis are viable new targets for asthma and its exacerbations.